Process for manufacture of L-DOPA ethyl ester

ABSTRACT

A process for manufacturing a highly purified, stable, non-hygroscopic, crystalline composition of L-DOPA ethyl ester. The L-DOPA ethyl ester is an active ingredient in many pharmaceutical preparations for the treatment of patients suffering from Parkinson&#39;s Disease and related indications.

[0001] This application claims the priority of U.S. ProvisionalApplication No. 60/107,820, filed Nov. 10, 1998, the contents of whichare hereby incorporated by reference into this application.

[0002] Throughout this application, various references are identified byauthors and full citation. Disclosure of these publications in theirentireties are hereby incorporated by reference into this application tomore fully describe the state of the art to which this inventionpertains.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The present invention relates to a process for manufacturing ahighly purified, stable, non-hygroscopic, crystalline composition ofL-DOPA ethyl ester. The L-DOPA ethyl ester (also known as LDEE) is anactive ingredient in many pharmaceutical preparations for the treatmentof patients suffering from Parkinson's disease and related indications.

[0005] 2. Description of Related Art

[0006] Typically Parkinsonian patients are routinely treated with acombination of levodopa (L-DOPA) and a DOPA decarboxylase inhibitor suchas carbidopa or benserazide. Unfortunately, after an initial period ofsatisfactory, smooth and stable clinical benefit from L-DOPA therapylasting on the average 2-5 years, the condition of many patientsdeteriorates and they develop complex dose-related as well asunpredictable response fluctuations. The causes of the responsefluctuations are probably multiple and complex, but pharmacokineticproblems (primarily faulty absorption of L-DOPA) may play a criticalrole. There is a correlation between the clinical fluctuations and theoscillations of L-DOPA plasma levels. Many of the problems are a resultof the unfavorable pharmacokinetic properties of L-DOPA, i.e., very poorsolubility, poor bio-availability and short half-life in vivo.

[0007] A more suitable L-DOPA ester for therapy would be the L-DOPAethyl ester. However, it has been difficult to develop the L-DOPA ethylester in a form suitable for pharmaceutical use:

[0008] “In view of the potential toxicity that might arise from methanolformation the ethyl ester would ideally have been most suitable forassessment in humans. However, the ethyl ester could not be crystallizedas its hydrochloride salt because of its hygroscopic potential. Themethyl ester was therefore developed for use in humans.” Stocci, F. etal, Movement Disorders, 7:249-256, (1992); at 254.

[0009] L-DOPA ethyl ester is described in the literature as thehydrochloride salt. However, it is difficult to isolate as a crystallinesalt and therefore was described as an amorphous solid (Fix, et al.,Pharm. Research 6(6):501-505 (1989)) which is not suitable forpharmaceutical use. Cooper, et al., Clinical Neuropharmacology 7:88-89(1984) note that L-DOPA ethyl ester hydrochloride salt is hygroscopicand difficult to crystallize during synthesis. Clearly, a pure, stable,non-hygroscopic form of L-DOPA ethyl ester is needed for pharmaceuticalpurposes.

[0010] Salts and esters of L-DOPA, including the L-DOPA ethyl ester, arementioned in Patent GB 1,342,286 for the treatment of alopecia. The onlydisclosure regarding the nature of the L-DOPA ethyl ester is that it canbe prepared from L-DOPA by conventional methods. However, as notedabove, preparation of L-DOPA ethyl ester by conventional methods yieldsa product which is not suitable for pharmaceutical use due to itsimpurity, its hygroscopicity, and its lack of stability.

[0011] Great Britain Patent No. 1,364,505 and corresponding U.S. Pat.No. 3,803,120, assigned to Hoffman-La Roche, describe the synthesis ofL-DOPA ethyl ester hydrochloride salt and free base. This compound isused as an intermediate in the synthesis of other compounds and is notcharacterized in the patent specification. In agreement with theliterature (Fix, et al., Pharm. Research 6(6):501-505 (1989); andCooper, et al., Clin. Pharmacol. 7:88-89 (1984)) we have found that theL-DOPA ethyl ester hydrochloride salt synthesized by the methodsdescribed in these patents is hygroscopic, not stable, difficult tocrystallize, and, as a result, difficult to purify. This material cannotbe used for pharmaceutical compositions. Likewise, the L-DOPA ethylester free base as prepared in these two patents is impure and notstable and thus also is not suitable for pharmaceutical compositions. Atbest it can be used as a synthetic intermediate for further chemicalsynthesis as described in the cited patents.

[0012] Two references note the synthesis of racemic ethyl ester.(Ginssburg, et al., Zh. Obshch. Khim. 39:1168-1170 (1969) and Venter, etal., S. Afr. Tydskr. Chem. 31:135-137(1978)). Neither of thesereferences prepare crystalline L-DOPA ethyl ester in a form suitable forpharmaceutical use and certainly there is no teaching or suggestion ofthe preparation of crystalline L-DOPA ethyl ester in a form suitable forpharmaceutical use. Both references prepare the material as anintermediate for the synthesis of other materials of interest.

[0013] More recently, Milman et al. (U.S. Pat. No. 5,354,885) describeda new process for preparing pharmaceutically acceptable, crystalline,non-hygroscopic L-DOPA ethyl ester as free base. The Milman processprovides L-DOPA ethyl ester of high purity, wherein at least 97% byweight is the L-DOPA ethyl ester while L-DOPA, as an impurity, ispresent in less than 1% by weight of the composition.

[0014] The crystalline, non-hygroscopic L-DOPA ethyl ester compositionproduced according to the Milman process is highly stable and remains asat least 97% by weight L-DOPA ethyl ester after incubation for 6 monthsat 40° C. The availability of L-DOPA ethyl ester in such high puritymade feasible the preparation of pharmaceutical compositions of L-DOPAethyl ester, which compositions could not be successfully developed on acommercial scale until the development of the process.

[0015] The potential for increased demand of highly purified L-DOPAethyl ester described in the U.S. Pat. No. 5,354,885, warrants researchto find a simpler, more economical process for producing L-DOPA ethylester of high purity. While the Milman process produced a highlypurified L-DOPA ethyl ester, the process is lengthy and complicatedbecause it involves extraction steps.

[0016] The Milman process comprises reacting L-DOPA with ethanol in thepresence of thionyl chloride or an acid catalyst to yield crude L-DOPAethyl ester hydrochloride. Then volatiles are removed from the crudeL-DOPA ethyl ester hydrochloride by vacuum distillation. The residue isthen dissolved with water containing a suitable antioxidant and the pHis adjusted to between 6.0 and 7.0 using a suitable base to yield asolution containing L-DOPA ethyl ester free base. To obtain the freebase in the solvent phase, the solution is extracted with a suitablesolvent in the presence of a suitable antioxidant. The solvent phase isthen concentrated at a temperature lower than 40° C. to form aprecipitate. The precipitate is then recrystallized in the presence of asecond suitable solvent containing a second suitable antioxidant toyield the composition of pharmaceutically acceptable, crystalline,non-hygroscopic L-DOPA ethyl ester free base.

[0017] The present invention discloses an unexpectedly simpler processfor manufacturing a composition comprising pharmaceutically acceptable,crystalline, non-hygroscopic L-DOPA ethyl ester as free base in anamount which is at least 95% by weight of the composition and L-DOPA inan amount which is less than 2% by weight of the composition.

SUMMARY OF THE INVENTION

[0018] This invention provides a novel and simplified process forpreparing a composition comprising pharmaceutically acceptable,crystalline, non-hygroscopic L-DOPA ethyl ester as free base in anamount which is at least 95%, and preferably 97% and more preferably 98%by weight of the composition and L-DOPA in an amount which is less than2% and preferably less than 0.5% by weight of the composition. Theprocess disclosed herein is significantly simpler and more economicalthan prior art processes while providing the L-DOPA ethyl ester of thesame high or higher purity as that of the Milman process disclosed inthe U.S. Pat. No. 5,354,885.

BRIEF DESCRIPTION OF THE FIGURES

[0019]FIG. 1: A block flow diagram summarizing the Milman Process forPreparing L-DOPA Ethyl Ester as disclosed in U.S. Pat. No. 9,354,885 toMilman et al. The process comprises six (6) main steps, including anextraction procedure (step (d)).

[0020]FIG. 2: A block flow diagram summarizing the Process forManufacture of L-DOPA Ethyl Ester according to the subject invention.The process according to the subject invention is distinguished from theMilman process of FIG. 1 because it achieves the same or higher purityof L-DOPA ethyl ester suitable for pharmaceutical use in less steps.

DETAILED DESCRIPTION OF THE INVENTION

[0021] This invention provides a process for preparing a compositioncomprising pharmaceutically acceptable, crystalline, non-hygroscopicL-DOPA ethyl ester as free base in an amount which is at least 95% byweight of the composition and L-DOPA in an amount which is less than 2%by weight of the composition. This process comprises the following steps(a) through (f):

[0022] (a) reacting L-DOPA with ethanol in the presence of thionylchloride or an acid catalyst to produce a solution of crude L-DOPA ethylester salt;

[0023] (b) removing any residual volatiles from the solution of crudeL-DOPA ethyl ester salt produced in step (a);

[0024] (c) diluting the solution from step (b) with water, and adding acosolvent and a suitable antioxidant;

[0025] (d) adding a suitable base to the solution from step (c) undercontrolled conditions to precipitate a crude L-DOPA ethyl ester freebase;

[0026] (e) drying the precipitated crude L-DOPA ethyl ester free base ofstep (d); and

[0027] (f) recrystallizing the dried, precipitated crude L-DOPA ethylester free base from step (e) in the presence of a suitable solventcontaining an antioxidant at a temperature of less than 10° C. toproduce the composition of pharmaceutically acceptable, crystalline,non-hygroscopic L-DOPA ethyl ester free base.

[0028] In one embodiment of the invention, the acid catalyst of step (a)is hydrogen chloride or toluenesulfonic acid. In the preferredembodiment of the invention, the acid catalyst of step (a) is hydrogenchloride.

[0029] In one embodiment of the invention, the crude L-DOPA ethyl estersalt produced in step (a) is crude L-DOPA ethyl ester hydrochloride.

[0030] In one embodiment of the invention, the removing of residualvolatiles from step (b) is effected by vacuum distillation.

[0031] In one embodiment of the invention, the residual volatiles fromstep (b) are ethanol and excess HCl.

[0032] In one embodiment of the invention, the cosolvent of step (c) istoluene.

[0033] In one embodiment of the invention, a suitable antioxidant ofstep (c) is selected from a group comprising ascorbic acid, sodiumsulfite, sodium metabisulfite, propyl gallate, and vitamin E. In aspecific embodiment of the invention, the antioxidant of step (c) issodium metabisulfite.

[0034] In one embodiment of the invention, a suitable base of step (d)may be an organic or inorganic base such as sodium hydroxide or ammoniumhydroxide. In a specific embodiment of the invention, a suitable base ofstep (d) is sodium hydroxide.

[0035] In one embodiment, the addition of a suitable base in step (d)effects an adjustment in the pH of the solution to a pH range betweenabout 5.0 and about 9.0 to precipitate a crude L-DOPA ethyl ester freebase.

[0036] In a specific embodiment, the addition of a suitable base in step(d) effects an adjustment in the pH of the solution to a pH rangebetween 6.5-8.0 to precipitate a crude L-DOPA ethyl ester free base.

[0037] In one embodiment of the invention, the controlled conditions forstep (d) are conditions in which addition of the base solution is slowlyperformed in a nitrogen atmosphere, and a trace amount of L-DOPA ethylester is added to induce formation of precipitate.

[0038] In one embodiment of the invention, the drying process in step(e) of the precipitated crude L-DOPA ethyl ester base from step (d) iseffected by azeotropic distillation.

[0039] In one embodiment of the invention, a suitable solvent of step(f) is selected from a group consisting of ethyl acetate, methylenechloride, or toluene. In a specific embodiment, the suitable solvent ofstep (f) is ethyl acetate.

[0040] In one embodiment of the invention, an antioxidant of step (f) isselected from a group consisting of ascorbic acid,2,6-Di-tert-butyl-4-methylphenol (BHT), butylated hydroxy anisol (BHA),propyl gallate, and vitamin E. In a specific embodiment, an antioxidantfor step (f) is 2,6-Di-tert-butyl-4-methylphenol (BHT).

[0041] This invention also provides a process for preparing acomposition comprising pharmaceutically acceptable, crystalline,non-hygroscopic L-DOPA ethyl ester as free base in an amount which is atleast 95% by weight of the composition and L-DOPA in an amount which isless than 2% by weight of the composition, which process consistsessentially of:

[0042] (a) reacting L-DOPA with ethanol in the presence of hydrogenchloride (HCl) to produce a solution of crude L-DOPA ethyl esterhydrochloride;

[0043] (b) removing ethanol and excess HCl from the solution of crudeL-DOPA ethyl ester hydrochloride produced in step (a);

[0044] (c) diluting the solution from step (b) with water, toluene, andsodium metabisulfite;

[0045] (d) adding a suitable base to the solution from step (c) undercontrolled conditions to precipitate a crude L-DOPA ethyl ester freebase;

[0046] (e) drying the precipitated crude L-DOPA ethyl ester free basefrom step (d); and

[0047] (f) recrystallizing the dried, precipitated crude L-DOPA ethylester free base from step (e) in the presence of a suitable solventcontaining an antioxidant at a temperature of less than 10° C. toproduce the composition of pharmaceutically acceptable, crystalline,non-hygroscopic L-DOPA ethyl ester free base.

[0048] In one embodiment of the process, the amount of hydrogen chloridegas of step (a) is between 1-3 equivalents.

[0049] In another embodiment of the process, the amount of hydrogenchloride gas of step (a) is between 1.75-2 equivalents.

[0050] In one embodiment of the process, the base solution in step (c)is sodium hydroxide (NaOH) solution or ammonium hydroxide (NH₄OH).

[0051] In another embodiment of the process, the base solution in step(c) is sodium hydroxide (NaOH) solution.

[0052] In another embodiment of the process, the controlled conditionsfrom step (d) are conditions in which addition of the sodium hydroxidesolution is slowly performed in a nitrogen atmosphere, at a reactiontemperature between 10-30° C. and a trace amount of L-DOPA ethyl esteris added to induce formation of precipitate.

[0053] In a further embodiment of the process, the controlled conditionsfrom step (d) are conditions in which addition of the sodium hydroxidesolution is slowly performed in a nitrogen atmosphere, at a reactiontemperature between 25-30° C. and a trace amount of L-DOPA ethyl esteris added to induce formation of precipitate.

[0054] In a specific embodiment, the addition of a suitable base in step(d) effects an adjustment in the pH of the solution to a pH rangebetween 6.5-8.0 to precipitate a crude L-DOPA ethyl ester free base. Inanother specific embodiment, the addition of a suitable base in step (d)effects an adjustment in the pH of the solution to a pH range between7.6 and 7.8 to precipitate a crude L-DOPA ethyl ester base.

[0055] This invention will be better understood from the ExperimentalDetails which follow. However, one skilled in the art will readilyappreciate that the specific methods and results discussed are merelyillustrative of the invention as described more fully in the claimswhich follow thereafter.

[0056] Experimental Details

[0057] Description of the Process

[0058] A process for preparing a composition comprising pharmaceuticallyacceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free basein an amount which is at least 95%, and preferably 97% and morepreferably 98% by weight of the composition and L-DOPA in an amountwhich is less than 2% by weight of the composition, which processcomprises detailed steps A-H:

[0059] A. Reacting L-DOPA with ethanol in the presence of 1.75-2equivalents HCl gas. The amount of HCl gas is not catalytic since oneequivalent reacts with the amino group of L-DOPA.

[0060] B. Removing the volatiles (ethanol and excess HCl) from the crudeL-DOPA ethyl ester hydrochloride.

[0061] C. Diluting the solution with water, adjusting the pH to 2-3 mostpreferably with 5N NaOH solution (at this pH range L-DOPA ethyl ester isstable in the solution and will not decompose back to L-DOPA during thedistillation of the reaction mixture). 13% NH₄OH solution can also beused for the precipitation of L-DOPA ethyl ester base.

[0062] D. Adding toluene as a cosolvent (prevents the sticking of theL-DOPA ethyl ester crude at the walls of the reactor during theprecipitation), adjusting pH to 4-5, adding a suitable antioxidant suchas sodium metabisulfite and purging out the air from the reactor byusing a continuous stream of nitrogen gas.

[0063] E. Adjusting the reaction temperature to 10-30° C. (mostpreferably to 25-30° C.) correcting the pH to 6.5-6.7 and seeding withL-DOPA ethyl ester to induce crystallization.

[0064] F. Precipitating L-DOPA ethyl ester base by controlled (slow)addition of the base solution until pH 7.4-8.0 (most preferably 7.6-7.8)and collecting the precipitate at 5° C.

[0065] G. Drying the water from the wet precipitate by azeotropicdistillation with toluene. If wet L-DOPA ethyl ester is dried in astainless steel vacuum oven, decomposition of the material results.

[0066] H. Recrystallizing the dried precipitate in the presence of ethylacetate containing BHT as antioxidant.

[0067] Synthesis of Crude L-DOPA Ethyl Ester

[0068] Absolute ethanol (395 g, 500 ml, 8.58 moles, 17 eq.) and L-DOPA(100 g, 0.507 moles, 1 eq.) are introduced into 1L reactor. The batch iscooled to 15° C. and HCl (g) (37.01 g, 1.014 mole, 2 eq.) is bubbledinto the reaction mixture at 15-30° C. The reaction is heated to reflux(79° C.) and kept at reflux for 3 hours. The batch is then cooled to 40°C. and 350-400 ml of solvent is distilled out under vacuum during 1.5-2hours (50 mbar, jacket temperature 60° C.). Deionized water (220 ml) isintroduced, the pH of the solution is adjusted to 2-3 with 5N NaOHsolution (65 ml) and 170 ml of the reaction mixture is distilled outduring 1.5-2 hours (50 mbar, jacket temperature 50° C.). Toluene (20 ml)is added to the resulting solution, the pH of the solution is adjustedto pH 4-5 with 5N NaOH solution and sodium metabisulfite (2 g, 2% w/w)is added. The operations from this stage on are done at nitrogenatmosphere. The temperature of the reaction is adjusted to 25-30° C.,the pH is adjusted to 6.5-6.7 with 5N NaOH and the solution is seededwith L-DOPA ethyl ester (1 g). The precipitation is continued bycontrolled addition of 5N NaOH solution (70 ml/hr.) until pH 7.6-7.8,the reaction mixture cooled to 520 C. and kept at this temperature forone hour. The precipitate is collected by filtration and washed with(2×40 ml) cold water. The crude wet precipitate is dried by azeotropicdistillation of the water with toluene (500 ml) under vacuum (50 mbar,jacket temperature 25-45° C.) until no more water is distilled out. Themixture is cooled to ambient temperature, L-DOPA ethyl ester (crude) iscollected by filtration, washed with toluene and dried in a vacuum ovenat 30-35° C. until constant weight. The yield of crude material is 85%.

[0069] Synthesis of Crystalline L-DOPA Ethyl Ester

[0070] Into 500 ml reactor are introduced L-DOPA ethyl ester crude (30g) and ethyl acetate which contains 0.01% BHT (150 ml, 5 volumesrelative to L-DOPA ethyl ester weight). The batch is heated to 50° C.during half an hour and kept at this temperature until a slightturbidity remained in the solution. The hot solution is filtered througha 0.2μ filter and returned into the reactor (the time elapsed from thebeginning of the crystallization until the end of filtration should notexceed 2.5 hours). The clear solution is cooled to 30° C. during 30 min.(seeded at 45° C. with L-DOPA ethyl ester, at 37-38° C. massivecrystallization is observed) then cooled to 5° C. during 1 hour and keptat this temperature for another 1 hour. L-DOPA ethyl ester (cryst.) iscollected by filtration, washed with 15 ml ethyl acetate which contains0.01% BHT under nitrogen and dried in a vacuum oven at 30-35° C. untilconstant weight. The crystallization yield is 85%. The overall yield is72%.

[0071] Purity of L-DOPA Ethyl Ester

[0072] The active ingredient resulting from the synthesis procedurecomprises (1) L-DOPA ethyl ester in an amount which is at least 95% byweight of active ingredient; and (2) L-DOPA in an amount which is lessthan 2% by weight of the active ingredient.

[0073] To increase the purity of the product, additional water may beadded. For example, performing the final crystallization in ethylacetate with 1% water will result in increased purity. The amount ofwater to be added is easily determinable by one skilled in the art.However, it is preferable to use only ethyl acetate since the additionof water will nearly always result in loss of yield.

[0074] Levodopa ethyl ester precipitated from water has surprisinglyhigher purity than levodopa ethyl ester isolated via the extractiveprocess (as performed in Milman et al.). The LDEE precipitation in watertakes place at low temperatures which prevents impurities such aslevodopa-levodopa ethyl ester and cyclic L-DOPA from evolving.Crystallization performed at higher temperatures (50° C.) tends to havea higher content of impurities. Therefore, the Milman process whichrequires extractive procedures at higher temperatures has a lower puritythan the present invention.

[0075] Moreover, crude levodopa ethyl ester produced after precipitationin the subject invention may in fact have higher purity than thelevodopa ethyl ester produced after crystallization for the reasonsstated above. The treatment with hot (50° C.) ethyl acetate may induceincreased production of impurities. However, the crystallization processis necessary for (1) controlling the particle size distribution (PSD)and (2) filtering each drug substance through a micron filter systemduring crystallization.

[0076] Physical Properties and Stability

[0077] L-DOPA ethyl ester as free base obtained by this process isstable, non-hygroscopic, crystalline and has a particle size in therange of: 18-180μ, with an average of less than 60μ.

[0078] The Novelties and Advantages of the Process

[0079] The main advantage of the process herein is the reduced number ofsteps which increases efficiency and economy. Comparison between theMilman process and the presently disclosed process shows a significantdifference in productivity. The Milman process and the process for thesubject invention have been summarized in FIGS. 1 and 2 respectively.

[0080] The Milman process comprises reacting L-DOPA with ethanol in thepresence of thionyl chloride or an acid catalyst to yield crude L-DOPAethyl ester hydrochloride. Any volatiles are then removed by vacuumdistillation, the residue is then dissolved with water containing asuitable antioxidant and the pH is then adjusted to between 6.0 and 7.0using a suitable base to yield a solution containing L-DOPA ethyl esterfree base. To obtain the free base in the solvent phase, the solution isextracted with a suitable solvent such as ethyl acetate, in the presenceof a suitable antioxidant. The solvent phase is then concentrated at atemperature lower than 40° C. to form a precipitate. Recrystallizationof the precipitate occurs in the presence of a second suitable solventcontaining a second suitable antioxidant to yield the composition ofpharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethylester free base.

[0081] The Milman process (FIG. 1) requires three-extractions andaddition of salt to the water phase at the second extraction. Theaddition of salt leaves the ethyl acetate saturated with salted waterwhich necessitates two additional washings. In addition to thecomplications of extractions and washings, the resulting ethyl acetatecontains about 7% water. Drying this ethyl acetate/L-DOPA ethyl estersolution is an involved step in the Milman process. Because most dryingagents interact with L-DOPA ethyl ester, azeotropic distillation is thebest route. Since azeotropic mixture of water and ethyl acetate containsa small amount of water, and since L-DOPA ethyl ester base is verysensitive to heat (producing two impurities, cyclic levodopa andlevodopa-levodopa ethyl ester), vacuum distillation is required. Vacuumdistillation is time consuming and the prior art process, as a whole,wastes solvent. These complications are detrimental to the resultingyield of the product. In fact, the Milman process results in only 50%yield, even though the reflux of L-DOPA with ethanol/HCl produces 96%L-DOPA ethyl ester hydrochloride in the reaction mixture. The remainingmaterial is in the water phase and decomposed to L-DOPA and otherbyproducts during the laborious work-up.

[0082] By contrast in the process of this invention (FIG. 2), afterremoval of volatiles, the next step is simply to adjust the pH of thesolution, add toluene and sodium metabisulfite, and then a solution ofsodium hydroxide in a controlled manner (temp., stirring speed, pH, rateof addition) to precipitate L-DOPA ethyl ester free base from theaqueous phase. The L-DOPA ethyl ester is then dried by azeotropicdistillation with toluene and crystallized from ethyl acetate containingBHT as antioxidant. The azeotropic distillation step disclosed in thisinvention eliminates the need to use ethyl acetate for isolation of thefinal product. Elimination of the distillation step results insignificant savings in solvents, their recovery, as well as time. L-DOPAethyl ester is not easily extracted since it is also soluble to acertain extent in water.

[0083] Compared to the Milman process, the presently disclosed processis simpler and shorter because the capacity of production in the samereactors in terms of volume of output and yield is tripled. In theMilman process, the extraction step extracts the product into theorganic phase (ethyl acetate) in a two system mixture (aqueous/organic),while in the presently disclosed process, the product is precipitatedfrom an aqueous phase since there is no organic phase. The fact that thesubject invention has a crystallization step starting from a dry crudelevodopa ethyl ester is a great advantage since reproducibility can beachieved, while in the Milman process, crystallization wasunpredictable.

[0084] Moreover, according to the present process, the precipitation ofL-DOPA ethyl ester is in water at an ambient temperature so that verypure compound is obtained in greater yield than previously in prior art.

What is claimed:
 1. A process for preparing a composition comprisingpharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethylester as free base in an amount which is at least 95% by weight of thecomposition and L-DOPA in an amount which is less than 2% by weight ofthe composition, which process comprises: (a) reacting L-DOPA withethanol in the presence of thionyl chloride or an acid catalyst toproduce a solution of crude L-DOPA ethyl ester salt; (b) removing anyresidual volatiles from the solution of crude L-DOPA ethyl ester saltproduced in step (a); (c) diluting the solution from step (b) withwater, and adding a cosolvent and a suitable antioxidant; (d) adding asuitable base to the solution from step (c) under controlled conditionsto precipitate a crude L-DOPA ethyl ester free base; (e) drying theprecipitated crude L-DOPA ethyl ester free base from step (d); and (f)recrystallizing the dried, precipitated crude L-DOPA ethyl ester freebase from step (e) in the presence of a suitable solvent containing anantioxidant at a temperature of less than 10° C. to produce thecomposition of pharmaceutically acceptable, crystalline, non-hygroscopicL-DOPA ethyl ester free base.
 2. The process of claim 1, wherein theacid catalyst of step (a) is hydrogen chloride or toluenesulfonic acid.3. The process of claim 2, wherein the acid catalyst of step (a) ishydrogen chloride.
 4. The process of claim 1, wherein the crude L-DOPAethyl ester salt produced in step (a) is L-DOPA ethyl esterhydrochloride.
 5. The process of claim 1, wherein the removing ofresidual volatiles in step (b) is effected by vacuum distillation. 6.The process of claim 5, wherein the residual volatiles removed in step(b) are ethanol and excess HCl.
 7. The process of claim 1, wherein thecosolvent of step (c) is toluene.
 8. The process of claim 1, wherein thesuitable antioxidant of step (c) is selected from a group consisting ofascorbic acid, sodium sulfite, sodium metabisulfite, propyl gallate, andvitamin E.
 9. The process of claim 8, wherein the suitable antioxidantof step (c) is sodium metabisulfite.
 10. The process of claim 1, whereinthe suitable base of step (d) is sodium hydroxide or ammonium hydroxide.11. The process of claim 10, wherein the suitable base of step (d) issodium hydroxide.
 12. The process of claim 1, wherein the addition of asuitable base in step (d) effects an adjustment in the pH of thesolution to a pH range between about 5.0 and about 9.0 to precipitate acrude L-DOPA ethyl ester base.
 13. The process of claim 12, wherein theaddition of a suitable base in step (d) effects an adjustment in the pHof the solution to a pH range between 6.5 and 8.0 to precipitate a crudeL-DOPA ethyl ester base.
 14. The process of claim 1, wherein thecontrolled conditions from step (d) are conditions in which addition ofthe base solution is slowly performed in a nitrogen atmosphere, and atrace amount of L-DOPA ethyl ester is added to induce formation ofprecipitate.
 15. The process of claim 1, wherein the drying of step (e)is effected by azeotropic distillation.
 16. The process of claim 1,wherein the suitable solvent of step (f) is selected from a groupconsisting of ethyl acetate, methylene chloride, and toluene.
 17. Theprocess of claim 16, wherein the suitable solvent of step (f) is ethylacetate.
 18. The process of claim 1, wherein the antioxidant of step (f)is selected from a group consisting of ascorbic acid,2,6-Di-tert-butyl-4-methylphenol (BHT), butylated hydroxy anisol (BHA)propyl gallate, and vitamin E.
 19. The process of claim 17, wherein theantioxidant of step (f) is 2,6-Di-tert-butyl-4-methylphenol (BHT).
 20. Aprocess for preparing a composition comprising pharmaceuticallyacceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free basein an amount which is at least 95% by weight of the composition andL-DOPA in an amount which is less than 2% by weight of the composition,which process comprises: (a) reacting L-DOPA with ethanol in thepresence of hydrogen chloride (HCl) to produce a solution of crudeL-DOPA ethyl ester hydrochloride; (b) removing ethanol and excess HClfrom the solution of crude L-DOPA ethyl ester hydrochloride produced instep (a); (c) diluting the solution from step (b) with water, toluene,and sodium metabisulfite; (d) adding a suitable base to the solutionfrom step (c) under controlled conditions to precipitate a crude L-DOPAethyl ester free base; (e) drying the precipitated crude L-DOPA ethylester free base from step (d); and (f) recrystallizing the dried,precipitated crude L-DOPA ethyl ester free base from step (e) in thepresence of a suitable solvent containing an antioxidant at atemperatures of less than 10° C. to produce the composition ofpharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethylester free base.
 21. The process of claim 20, wherein the amount ofhydrogen chloride gas of step (a) is between 1-3 equivalents.
 22. Theprocess of claim 21, wherein the hydrogen chloride gas of step (a) isbetween 1.75-2 equivalents.
 23. The process of claim 20, wherein thebase solution in step (c) is sodium hydroxide solution or ammoniumhydroxide.
 24. The process of claim 23, wherein the base solution instep (c) is sodium hydroxide solution.
 25. The process of claim 20,wherein the controlled conditions from step (d) are conditions in whichaddition of the sodium hydroxide solution is slowly performed in anitrogen atmosphere, at a reaction temperature between 10-30° C. and atrace amount of L-DOPA ethyl ester is added to induce formation ofprecipitate.
 26. The process of claim 25, wherein reaction temperatureis between 25-30° C.
 27. The process of claim 20, wherein the additionof a suitable base in step (d) effects an adjustment in the pH of thesolution to a pH range between 6.5 and 8.0 to precipitate a crude L-DOPAethyl ester base.
 28. The process of claim 28, wherein the addition of asuitable base in step (d) effects an adjustment in the pH of thesolution to a pH range between 7.6 and 7.8 to precipitate a crude L-DOPAethyl ester base.